DESCRIPTION: The long term goals of this research are to understand how estrogen and antiestrogens regulate human breast cancer cell proliferation, an how cells that initially require estrogen to proliferate eventually become estrogen independent and antiestrogen resistant. Attaining these goals is critical, since the development of estrogen independence and antiestrogen resistance is a major cause of treatment failure in breast cancer patients. On approach that will be taken is to compare regulation of the intracellular cyclin/CDK pathway that controls cell proliferation in the estrogen dependent breast cancer cell line MCF-7, in estrogen independent and antiestrogen resistant derivatives of MCF-7, and in a panel of other ER+ and ER- breast cancer cell lines. In addition, experiments will be carried out to determine whether perturbing the cyclin/CDK pathway can directly convert MCF-7 cells to estrogen independence and/or estrogen resistance. In Aim I, the regulation of protein levels and CDK activity will be compared in the cell lines described above. In Aims II-IV, the cyclin/CDK pathway will be disrupted in a variety of ways including inhibition of cyclin/CDK activity, inhibition of RB function, and overexpression of cyclin genes, and the effects of these perturbations on hormone dependence of fMCF-7 cells will be examined. These studies will identify important targets of estrogen and antiestrogen action, and suggest possible mechanisms by which breast tumors can become estrogen independent and antiestrogen resistant.